Because bimatoprost stimulated isolated scalp follicle growth in organ culture, where there is no possibility of involving alterations in blood supply, interactions with other skin tissues, or circulating cells, direct effects on follicles
via specific receptors in hair follicle cells are the most likely method of action. The saturation of the effect at receptor-relevant concentrations (
Fig. 3) and the ability of the potent prostamide antagonist, AGN 211336, with a pA[SUB]2[/SUB] of 7.6 against the prostamide receptor (
20), to block the stimulatory effects of bimatoprost on both hair growth parameters in this dynamic bioassay (
Fig. 3) also indicate a receptor-mediated response.
The presence of appropriate prostanoid receptors in human scalp hair follicles in vivo (Fig. 6 and Table 1), combined with the organ culture observations, strongly suggest that scalp follicles have the ability to respond with increased growth in vivo. The identification of genes for the known bimatoprost receptor, FP/altFP4 (30) in scalp hair follicles in vivo (Fig. 6 and Table 1), combined with the prostamide receptor antagonist's prevention of any effect (Fig. 3C), also indicate that bimatoprost acts directly on hair folliclesvia receptors within them. Studies in FP-deficient mice confirm FP gene expression is essential for bimatoprost effects on intraocular pressure in the eye (42). The location of FP protein (Fig. 5) and the gene expression of FP and splice variants altFP4 and altFP1 (Fig. 6 and Table 1) only in the mesenchyme-derived dermal papilla and CTS is particularly interesting. The dermal papilla determines the type of hair a follicle forms by producing paracrine signals to control other follicular functions (31, 32); the lower follicular CTS can replace this function (28). Reports of prostaglandin-metabolizing enzymes and FP in human scalp cultured dermal papilla cells (43, 44) support this localization in the dermal papilla. The absence of any relevant prostanoid receptors in the bulb keratinocytes, which form the hair or the melanocytes that produce the pigment and the bulge region, the site of epithelial (33) and melanocyte stem cells (34) strongly suggests that the dermal papilla is coordinating follicular responses of increased pigmentation and growth in anagen follicles. Both PGF[SUB]2α[/SUB] and prostamide F[SUB]2α[/SUB] bind to transmembrane G[SUB]α[/SUB]q protein-coupled receptors (Fig. 1), which trigger intracellular signaling, resulting in increased intracellular Ca[SUP]2+[/SUP] levels (30). Presumably, this will alter the gene expression of paracrine factors produced by the dermal papilla, which influence the activity of the bulb keratinocytes and melanocytes (see Fig. 7). This parallels the mechanism of androgen action in hair follicles (7, 25) and could include increasing production of stem cell factor (SCF), a pigment-stimulating factor reduced in androgenetic alopecia (45) and/or reducing that of TGF-β, an inhibitory factor associated with balding (46).
